The hunt for the master cow that will feed the world

LAURA DOMIGAN IS a chronicler of cows. Every biographical detail and pharmacological footnote could be crucial, so the biochemist has a long list of questions for the farmers she works with. Where was the cow raised? What did it eat? What did it look like? Which medicines did it take and why? How old was the cow when it was slaughtered?

Domigan knows enough to write a family history about these cows, but she’s more interested in what they leave behind when they die. Shortly after a cow has been slaughtered, one of her colleagues arrives at the abattoir with a Petri dish in hand and removes a tiny slither of muscle tissue from the carcass, bathing it in a salt solution to stop the cells within from bursting open or shrivelling up. The precious nugget is then packed in ice and ferried back to Domigan’s laboratory at the University of Auckland in New Zealand.

This is where the bovine biographies come in handy. Domigan’s job is to work out how to turn that collection of cells into hunks of meat grown in stainless steel bioreactors. From a Petri dish to a silo full of steaks, the hope is that one day this process can replace some of the 1.5 billion crop-guzzling, methane-burping cows on the planet today. At a glance, the formula for cultured – or lab-grown – meat is simple. Take some animal cells, feed them on a nutrient-filled broth so they duplicate lots of times, then alter that broth slightly so the cells turn into the constituent parts of meat: muscle, fat, and connective tissue. Perfect this recipe and we could – theoretically – satiate the entire planet’s hunger for burgers and steaks with cells taken from a single cow.

Getting those cells right is a make-or-break issue for the cultured meat industry. Start with the wrong cells and your vat full of would-be-burgers can very quickly turn into a sludge of proto-meat soup. Solve that problem and you’ve still got to work out how to grow those cells at a cost close to conventional meat and then build a whole production process to reliably brew up thousands of tonnes of meat a year. Distilling the essence of an animal into a slice of cells no bigger than a fingertip is a colossal challenge. So far, no one has managed to crack it.

For companies and academics, the only way of figuring all this out is to get up close and personal with a lot of cells. This means getting their hands on cell lines: reliable, well-studied and easy-to-access cells that anyone can experiment on. Cell lines are one of the most basic building tools in scientific research – in the biomedical industry, they’re absolutely everywhere. In the world of cultured meat, however, these much-needed cell lines either don’t exist or are locked up in the labs of a handful of cultured meat companies.

Some scientists fear that the lack of access to cell lines is holding the entire cultured meat industry back. The cellular blueprint for tomorrow’s factory-brewed burgers is out there somewhere – but, without access to cell lines, many of the people trying to make this future a reality are still fumbling around in the half-shadows.

THE LARGEST COLLECTION of cell lines in the world is in Manassas, Virginia. There, tucked safely away in a series of freezers, the headquarters of the American Type Culture Collection (ATCC) houses nearly 4,000 cell lines from over 150 species. For more than half-a-century, these cells have been the starting point for the development of vaccines, drugs and for the study of cancers and genes. Trace the history of any biomedical breakthrough back far enough and you will probably find a scientist reaching into a freezer to extract a vial of cells shipped from a collection like the ATCC.

Some cell lines seem to defy the most basic rule of biology: that every living thing must eventually die. Cells grow by dividing in two, but most cells taken from a living animal will only duplicate a limited number of times before they die. Some cell lines, however, can become immortalised – either spontaneously or with some tweaking in the lab – so they duplicate endlessly, producing near-identical copies of themselves for decades. Almost everything about these cell lines is well documented: their genes, which proteins they produce, how they grow and respond to different containers and solutions. The first immortal cell line was derived in 1951 – taken from the body of Henrietta Lacks, a woman dying of cervical cancer who had no idea that cells from her cervix would one day help scientists develop the polio vaccine, manufacture drugs and understand cancers. More than 50 million tonnes of HeLa cells – named after the woman they came from – have been grown over the last seven decades.

This immortality is what makes cell lines so useful. A scientist experimenting on HEK293 cells – human embryonic kidney cells first isolated in 1973 – can flick through research from decades ago and know that if they perform the same experiment on the HEK293 cells in their freezer they will probably get the same result. It’s like a builder coming across a half-built house. As long as they’re using the same bricks as the builder that went before them, they can see how everything fits together. But if they have to use a different material, they may as well just start from scratch.

When it comes to cultured meat, there is no equivalent to the ATCC. In fact, there are almost no widely-available cell lines at all. “There’s basically nowhere to start yet. If anyone wants to get into this field, it takes a significant amount of resources and time to acquire and characterise a cell line in-house,” says Elliot Swartz, a scientist at The Good Food Institute (GFI), a nonprofit that funds research into alternatives to animal protein. In February 2020, the GFI set up a scheme to let companies and researchers deposit their cultured meat cell lines with Kerafast – a Boston-based company that supplies the biomedical industries.

So far only one cell line has been banked as part of the scheme: an embryonic cell line from the European sea bass. It’s a start, Swartz says, but even he admits that cultured meat researchers aren’t exactly clamouring for sea bass cells. Swartz regularly gets emails from researchers asking if he knows where they can get their hands on animal cell lines. “Even cultured meat companies ask me this. I have nowhere to turn them. It’s a real problem.” The GFI has funded research to develop cell lines from chickens, cows, pigs and ducks but, because of the pandemic, work is already running behind schedule

With the right cell lines, cultured meat could go from an extremely niche food to a genuine rival to big beef. Bioreactors the world over would slosh with cultured steaks and sausages and our insatiable hunger for meat could be met not by environmentally ruinous mega-farms but by cutting-edge bioreactors with (potentially) a fraction of the environmental impact. Fail to find the right cell lines, however, and the cultured meat dream could remain the preserve of high-end dining and public relations events. To feed the world – and potentially save the planet – scientists need to find the perfect starting cells.

Cell lines from cows are the most in-demand. Not only is beef one of the world’s most popular meats, it has a higher carbon footprint than any other form of animal protein. It’s an obvious target for the cultured meat industry, which has long-positioned itself as a more environmentally-sustainable method of meat production. The problem is that until very recently scientists weren’t very familiar with the kinds of cow cells that the cultured meat industry needs. We’ve been turning cows into meat for tens of thousands of years, after all, but never needed to recreate this process in a bioreactor.

Although the first embryonic stem cell line in mice was derived in 1981, it wasn’t until 2018 that scientists repeated the trick with cattle embryonic stem cells. Embryonic stem cells are particularly relevant to the cultured meat industry because – like immortalised cell lines – they can duplicate indefinitely. Pablo Ross, one of the researchers that created that cattle stem cell line, says he has shared the cells with cultured meat companies and academics, and is happy to keep sharing them. Despite these efforts, there is still no widely-available store of relevant cattle cell lines anywhere in the world.

“Just having a cell line that you can bank and use for years and years and years is really important,” says Andrew Stout, a cultured meat researcher at Tufts University in Massachusetts. Since every cell type is different, researchers like Stout need to know some basic information about their cell lines to work out if they’d be a useful starting point for cultured meat. How quickly do the cells process their food and release waste? Do they easily turn into muscle fibres? Which nutrients do they require to grow?

Without any of this information on cow cells, cultured meat researchers have to turn to a source of muscle cells that science is familiar with: mouse cells. “We’re relying on a mouse cell because it’s an available mammalian muscle cell line. Really, it’s the only one,” says Stout. A lot of what we know about growing muscle cells in the lab comes from studies on a mouse cell line called C2C12 – originally derived from a slice of thigh muscle taken from a two-month-old mouse in 1977. C2C12 cells duplicate easily, aren’t too fussy about where they grow or what they’re fed on, and a fresh sample from a cell bank is only ever a few clicks away. In short, they’re everything that cow cell lines are not.

But C2C12 cells can only get us so far. They require different nutrients to cow cells, and any experiment on mouse cells will need to be repeated with cow cells to really prove its worth. “It’s a crutch that I think is okay, but one that I hope the field does away with sooner rather than later,” Stout says. Other cultured meat researchers agree that the days of experimenting on mouse cells are numbered, but this poses an even more challenging question about the future of the field. If the end goal is to create cow cell lines that will one day produce hundreds of times more meat than could ever be butchered from a single cow, which cells should we start with?

A FIELD OF cows in Limburg, the southernmost province of the Netherlands, holds one potential answer. This is where the cultured meat company Mosa Meat sources some of its cell lines, which start life as half-gram samples of muscle tissue taken from living cows. Founded in 2016 by Mark Post, the creator of the world’s first cultured burger, Mosa Meat is more willing than most companies to divulge some of the details about the cell lines that it is working on.

The company’s main focus is on primary cell lines – cells taken directly from a tissue sample that, unlike immortalised cell lines, can only grow for a limited period of time before they begin to die. Most cell types can only divide between fifty and sixty times before they break down – a theoretical limit that is even harder to reach when cells are taken out of their host animal and grown in bioreactors instead. If the cells reach this limit before you’re ready to turn them into muscle fibres and fat cells, then you might end up with a bioreactor sloshing with inedible meaty goo.

The leader of Mosa Meat’s cell biology team, Joshua Flack, says that they haven’t yet managed to make cells taken from muscle tissue divide 50 times. Something about growing cells in the lab seems to accelerate how they age. “A lot of our experiments relate to trying to understand why cells age or seem to show fast, premature ageing in plastic,” says Flack, who is now searching for ways to reverse or slow down that ageing. One option might be to remove – or add – certain molecules to the fluid that cells are grown in, to change the way that they respond to signals telling them to age. Another option might be to start with younger cows. Flack is working on an experiment comparing cells taken from the same animal at the age of three, six and 12 months. The idea is that if cells have spent less time dividing within an animal then they will have more divisions to spare once they’re removed from the body.

Domigan is also working with cells taken directly from muscle tissue. She’s leading a project, co-funded by the governments of New Zealand and Singapore, that’s attempting to establish some of the basics when it comes to cultured meat: primarily, how to get cells to divide rapidly and to develop into the right mix of muscle, fats and connective tissue that make up most meat. Neta Levon, vice president of research and development at Israeli cultured meat firm Aleph Farms, says the company will be able to produce thousands of tonnes of meat from a single cell sample taken from a living animal. One of the company’s cell banks includes cells taken from an American Angus cow, with full genetic tracing and documentation about the health of the animal – information that regulators (and customers) may well want to know about when it comes to selling cultured meat.

Faced with the problem of ageing cells, Mosa Meat has another team that is experimenting with genetically-engineered cell lines that can duplicate endlessly. This approach has a few advantages. First, it would mean that the company would never have to return to an animal to take another biopsy and could draw on an infinite supply of banked cells. Second, it would allow companies to tailor their production process to those exact cells. Third, the cells could also be engineered to make them grow more efficiently.

This last point is key. Right now, the cost of producing cultured meat is between 10,000 and 100 times higher than conventional meat, largely because of the expensive fluid called growth media that cells are grown in. Unless companies can find a way to reduce the cost of growth media, or use less of it, then cultured meat will remain eye-wateringly expensive. Genetic engineering might be one way to get around this. California-based Upside Foods – formerly called Memphis Meats – has applied for a patent that describes gene-editing cells so they produce one of the key components of growth media on their own.

Patent applications only hint at what companies might be working on, but both Flack and Stout agree that genetically-engineered cells might be the only way to drive down the costs of cultured meat. “I think that getting from $300,000 (£211,000) for a burger to $50 (£35) for a burger is going to be easier than getting from $50 to $2 (£1.40),” Stout says. “I’m not at all confident that, without improving the cells themselves, you can get to $2.”

But why stop at gene-editing cells to make them grow more efficiently? There are all kinds of funky things you could do with engineered cell lines. One idea Stout has is to edit chicken cells so they can express limonene – the oil that gives citruses their fruity aroma – to make lemon chicken at a cellular level. In 2020, he published a study detailing how he inserted three genes into cow muscle cells so they produced antioxidants that mitigate some of the negative effects of eating red meat. Take them out of an animal, and cells could become a blank canvas for new kinds of culinary creativity.

WITHOUT CELL LINES to start with, researchers are having to go it alone. Stout got his cow stem cells from his university’s veterinary school, but not every lab has that kind of access, and even that source of cow stem cells is much less useful than the holy grail: a cell bank of immortalised cow cells that anyone can access.

There are at least 40 companies vying to bring cultured meat to the market – and venture capital funding is pouring in from all angles. Eat Just, which became the first cultured meat company to sell its products in a restaurant after Singapore approved its cultured chicken at the end of 2020, has raised £318 million in funding in 2021 alone. In February, Mosa Meat closed its Series B funding round after securing £59m and a month later another Dutch firm, Meatable, announced it had raised a further £33m.

Cell lines are the secret sauce of the cultured meat industry, so it’s unsurprising that most companies are keeping theirs under wraps. A spokesperson for Eat Just said that the company could not share details about its cell lines for intellectual property reasons. Neta Lavon at Aleph Farms said that the company is working with pre-embryonic stem cells, but that it had no plans to share its cell lines in the short-term. Other cultured meat companies contacted did not make themselves available for interview.

“One of the things I don’t like about the cultured meat industry is how lots of the best research, probably the furthest-advanced research, is all locked up in companies that aren’t saying anything,” says Flack. Swartz says three cultured meat firms have contacted him about taking part in the GFI’s cell line banking project, which lets companies retain their intellectual property, but none of them have deposited cell lines yet. Companies are likely to only use the best-performing cell lines for their meat production, Swartz says, leaving other less developed cell lines unused. “This gives them an opportunity, in my opinion, to share those cell lines at no cost.”

In the meantime, companies that specialise in cell lines might fill the gap. Edinburgh-based Roslin Technologies usually produces cell lines for toxicology and drug screening, but now sells pig stem cells to the cultured meat industry. It already has a contract with one cultured meat firm and has evaluation licenses with other companies that are trialling its stem cells. The cells the company is licensing are called induced pluripotent stem cells – cells that have been reprogrammed back into a state where they can develop into many different types of cells. Because this reprogramming doesn’t alter the genetic makeup of the cell they might escape European Union regulations that limit the sale of any genetically modified foods, says Richard Freeman, commercial manager at Roslin Technologies.

Freeman adds that supplying the cultured meat industry is likely to be a big part of the company’s future. “Bovine is going to be pretty key for us going forward, because it's the thing that everyone is interested in,” he says. While the first-wave of cultured meat companies have tended to develop their own cell lines and growth media, there are now a number of companies that concentrate on selling directly to the cultured meat industry – there are already at least eight firms that specialise in creating growth media.

But the road to success for cell line specialists isn’t straightforward. In April 2021, entrepreneur Sofia Giampaoli had to dissolve Cell Farm Food Tech, the cell line startup she co-founded in 2019. Despite securing seed funding, Giampaoli says that investors were more interested in companies that develop final products rather than selling to industries. Now she’s working on a venture that can bring a new product to market more quickly while also working on cell lines.

For now, researchers and companies looking for the starting materials of cultured meat still need to do the tricky work of isolating a cell line themselves, or else cajole a friendly researcher into sharing their work. But if cultured meat is going to scale enough to dent the trillion-dollar global meat trade, then sooner or later regulators, consumers and producers will all have to get very familiar with the cell lines behind our steaks. And for Domigan, that means going back to those cow biographies and understanding exactly where her cells came from. “You don’t know what information is important, and if we’re going to put effort into developing technology then you need all the information right from the beginning.”

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